Fellows’ Corner
Authors: Robert M. Wilechansky
Journal: Hepatology (2023)

Keeping up with an ever-evolving literature during GI and hepatology training is by no means an easy task. As this year's Hepatology Editorial Fellow, I aim to streamline this process by selecting a few recent articles each quarter that I found particularly impactful. Choosing from so many exciting studies was quite challenging; the following 3 papers describe meaningful developments for diagnostics and therapeutics in hepatology. A recent clinical trial investigated the effect of a combination oral tropifexor (TXR) plus oral cenicriviroc (CVC) versus either as monotherapy in metabolic dysfunction–associated steatohepatitis (MASH).1 As background, there are currently no approved therapies for MASH. After numerous clinical trials over the last decade, many therapies have either been ineffective or failed to meet histological end points, such as reduced fibrosis. The investigators in this study sought to leverage multiple mechanisms to target the complex pathophysiology of MASH. TXR is a farnesoid X receptor agonist, thought to regulate bile acid metabolism and modulate regeneration during liver injury, while CVC is an inhibitor of CCR2 and CCR5, which are chemokine receptors involved in recruiting inflammatory cells to the liver. These agents were used in the TANDEM study, a 48-week, multicenter, double-blind, phase 2b randomized controlled trial in 65 centers across 17 countries. A total of 193 Adults with histologic MASH and F2 or F3 fibrosis were randomized to 4 treatment arms (higher-dose TXR + CVC, lower dose TXR + CVC, TXR monotherapy, and CVC monotherapy); 158 patients completed the study. Both combination groups met the primary safety end points; 1 serious adverse event was attributed to the treatment. Notably, 40% of patients in the higher-dose TXR group reported pruritus, a known side effect of farnesoid X receptor agonists. For the secondary end point of histologic improvement, there was no difference in response rates across groups; about 30% of participants had at least a 1-point improvement in fibrosis, and 13%–25% had resolution of steatohepatitis. Post hoc digital pathology quantification revealed a dose-dependent additive effect on fibrosis reduction in the combination groups. Overall, the investigators showed that agents that target steatohepatitis and fibrosis in MASH may be safely combined, and we can be optimistic about the future of similar combination trials. Though the groups did not differ, and concerns may be raised about the side effects of pruritus, a substantial proportion of patients met histological end points. Finally, the advent of artificial intelligence-supported digital quantification may enable more accurate measurement of histologic end points in future studies. Primary biliary cholangitis, while rare, can be debilitating and has few treatment options. The ENHANCE study is a welcome development conducted at 111 sites in 21 countries.2 This phase 3, double-blind, placebo-controlled, randomized controlled trial investigated the safety and efficacy of oral seladelpar, a selective peroxisome proliferator-activated receptor-δ agonist in patients with primary biliary cholangitis who did not tolerate or did not respond to ursodeoxycholic acid. Eligible patients (n = 265) were randomized 1:1:1 to receive placebo or seladelpar 5 mg or 10 mg. The study was unfortunately stopped at 3 months due to an adverse event in another trial that was ultimately deemed unrelated to the drug. Despite this, at 3 months, 78% and 58% of participants in the high-dose and low-dose treatment groups, respectively, met the primary composite end point (alkaline phosphatase < 1.67 times upper limit of normal, ≥ 15% alkaline phosphatase decrease from baseline, and total bilirubin ≤ upper limit of normal), compared to 12% in the placebo group (P < 0.0001 for both). Importantly, there was also a dose-dependent increase in the number of patients reporting a decrease in pruritus, and the mean reduction of pruritus in the seladelpar 10 mg group was significantly greater than placebo. Seladelpar also led to durable reductions in liver biochemistry, IgM, and lipids at 3 and 6 months compared to placebo. Serious adverse events were rare. The most common adverse event was pruritus; notably, this was most frequently reported in the placebo group. For patients with primary biliary cholangitis, seladelpar can potentially improve disease activity and quality of life, and other selective peroxisome proliferator-activated receptor agonists are concurrently in clinical trials. I eagerly await the results of longer-term trials to evaluate the effects of this drug class on important clinical outcomes, both as monotherapy and potentially in combination with other novel agents. Preventive medicine in hepatology is an area that warrants continued investigation and innovation. In the last decade, the "omics" sciences have emerged as methodologies for predictive biomarker development that may obviate the need for invasive diagnostic procedures. Earlier this year, a nested study within the PREDESCI cohort utilized serum metabolomics to examine clinical outcomes.3 The original PREDESCI study was a randomized controlled trial of nonselective beta blockers versus placebo in compensated patients with clinically significant portal hypertension, defined as HVPG ≥10 mm Hg. The investigators in the nested study used serum liquid chromatography-mass spectrometry metabolomics in a subset of 167 patients with compensated cirrhosis and clinically significant portal hypertension to predict the likelihood of the primary end point of the PREDESCI study (a composite of hepatic decompensation or liver-related death). The authors created a clinical predictive model using the Child-Pugh score, baseline HVPG, and NSBB treatment status. Subsequently, they used univariate Cox regression to select the top 20 out of 231 metabolites, followed by stepwise Cox regression yielding 2 metabolites (ceramide d18:1/22:0 and methionine) that were added to the clinical model. The inclusion of these two metabolites significantly increased the AUROC (0.81 vs. 0.75, DeLong P = 0.03). Moreover, a third, "noninvasive" model including the metabolites, Child-Pugh score, and NSBB status performed just as well as the equivalent model that included HVPG measurement (AUROC 0.79 vs. 0.81, DeLong P = 0.3). Though the results have not yet been validated in external cohorts, this study illustrates the potential of metabolomics (and other related "omics" platforms) to augment our ability to predict clinical outcomes in place of invasive procedures. Moving forward, metabolomics assay performance, selection of targeted metabolites, and metabolomics analysis methodologies should become more standardized to facilitate transition into clinical practice. While the first two studies serve as benchmarks in drug development for liver conditions that urgently need targeted therapies, the last signifies the expanding set of diagnostic and predictive instruments that hepatologists may have available in the coming years. Each offers promising new directions for future work that could improve outcomes for patients with liver disease.